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1 Department of Medicine, University of California at San Diego, San Diego, CA, USA
2 Department of Pschiatry, University of California at San Diego, San Diego, CA, USA; The Polymorphism Research Laboratory, University of California at San Diego, San Diego, CA, USA
3 Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
4 Department of Medicine, University of California at San Diego, San Diego, CA, USA; Department of Pharmacology, University of California at San Diego, San Diego, CA, USA; The Polymorphism Research Laboratory, University of California at San Diego, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: doconnor{at}ucsd.edu.
Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)n. We asked whether variation at (TCAT)n may influenced the autonomic nervous system and its response to environmental stress. To understand the role of heredity in such traits, we turned to a human twin study design. Both biochemical and physiological autonomic traits displayed substantial heritability (h2), up to h2=56.8±7.5% (p<0.0001) for norepinephrine secretion, and h2=61±6% (p<0.001) for heart rate. Common (TCAT)n alleles, particularly (TCAT)6 and (TCAT)10i, predicted such traits (including catecholamine secretion, as well as basal and post-stress heart rate) in allele copy number dose-dependent fashion, though in directionally opposite ways, indicating functional allelic heterogeneity. (TCAT)n diploid genotypes (e.g., [TCAT]6/[TCAT]10i) predicted the same physiological traits, but with increased explanatory power for trait variation (in contrast to allele copy number). Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)10i allele on both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)6 allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, "intermediate phenotypes" in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the tyrosine hydroxylase locus exerts a powerful, heritable effect on autonomic control of the circulation, and that such variation may have implications in later development of cardiovascular disease traits such as hypertension.
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